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General Pharmacology > Advanced Pharmacokinetics > Flashcards

Advanced Pharmacokinetics Flashcards

1
Q

Phase I metabolism

A

creates a chemical functional group on a drug

(eg many Cyt-p450 reactions)

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2
Q

Phase II metabolism

A

conugation of a water soluble molecule to a functional group on a drug

(makes drug more water soluble and/or inactive)

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3
Q

Most drugs distribute

A

rapidly; reach a distribution equilibrium, behave as if in a single compartment

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4
Q

Rate of drug elimination is proportional to

A

concentration in plasma (first-order kinetics)

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5
Q

Drugs given by rapid IV administration disribute and are eliminated by

A

rapidly; first-order kinetics (proportional to concentration in plasma)

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6
Q

In short-term IV infusion, drug is administered

A

at a constant rate

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7
Q

In short-term IV infusion, drug is distributed and eliminated

A

rapidly; first-order

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8
Q

How does drug concentration rise in rapid-IV?

A

rapidly, administered all at once

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9
Q

How does drug concentration increase in short-term IV?

A
  • does not rise constantly
    • as concentration increases, rate of elimination increases
    • tf as it accumulates, it accumulates slower and slower because elimination is increasing
    • concentration rises, then plateaus
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10
Q

What happens to drug concentration when short-term IV infusion is stopped?

A

eliminated exponentially (as if it had been a bolus/rapid-IV administration)

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11
Q

What is the difference in peak concentration between rapid and short-term IV?

A

peak is much higher in rapid bc administered all at once; short-term is infused gradually, tf peak concentration will never be as high as rapid IV

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12
Q

What feature of drug concentration differentiates short and long term IV infusion?

A

long term IV infusion reaches a steady state drug concentration; short term IV infusion does not

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13
Q

The steady-state concentration of drug in long term IV infusion is proportional to

A
  • the infustion rate
    • rate of infusion = rate of elimination
  • tf easy to ‘dial up’ a particular concentration in a patient by changing the rate of infusion:
    • infusion rate = Css
    • 2x infusion rate = 2x Css
    • 0.5x infusion rate = 0.5x Css
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14
Q

How are multiple dosing and long term IV administrations related?

A

pattern of accumulation in long term IV infusion is the same if the drug is given at a constant rate or in a series of multpile doses; both are a constant rate

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15
Q

The dosing interval of most drugs is

A

half-life

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16
Q

What is a loading dose?

A

volume distribution x concentration

use to establish a steady-state blood concentration before administering multiple doses of a drug (usually with a long half-life)

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17
Q

Absorption of orally administered drugs is primarily

A

lipid diffusion in the small intestine

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18
Q

Absorption of orally administered drugs depends on

A

concentration in the small intestine (greater concentration = greater drive for absorption)

19
Q

Elimiantion rate of orally administered drugs depends on

A

concentration in the blood (first order elimination)

20
Q

What are the features of oral administration?

A
  • peak concentration is not as high as IV
    • some drug is eliminated during absorption
    • not all drug may be absorbed from GI (absorption is not a factor in IV)
    • some may be first-pass metabolised in the liver, reducing concentration in the blood
21
Q

What is bioavailability?

A
  • proportion of active drug that enters the systemic circulation
  • (100% with IV, less via other routes)
  • affected by:
    • how much is absorbed
    • how much of the drug undergoes:
      • first pass hepatic metabolism (oral admin)
      • local metabolism (eg in GI prior to absorption, at skin or muscle for intramuscular injection)
22
Q

Bioavailability is calculated by

A
  • area under the concetrantio vs time curves for IV and oral administration:
    • (AUC-oral/AUC-IV) X 100%
  • if oral bioavalability is less than IV, need to administer more drug to get the same dose:
    • IV = 100mg; oral = 75%
    • 100/0.75 = 133mg oral dose
23
Q

What are the factors that complicate drug use?

A
  • unusual drug behaviour
  • interpatient variability
24
Q

What are unusual drug behaviours?

A
  • low bioavailability - drug is sensitive to variability
  • slow distribution such that some is eliminated during distribution
  • sufficiently high concentrations of drug to saturate elimination processes, making elimination rate constant (zero-order kinetics)
25
Q

How does low bioavailability increase sensitivity to variability in concentration?

A
  • 90+/-5%, variation is (95-85)/85 = 12%
  • 10+/-5%, variation is (15-5)/5 = 200% –> pt ends up with twice as much drug as another
26
Q

Drugs with low bioavailability need to be administered by

A

Routes that avoid first-pass metbolism:

  • skin (patches)
  • lungs (gas)
  • nose
  • rectum
  • subcutaneous injection

these may have absorption factors that contribute to bioavailability; IV avoids both issues but not always appropriate

27
Q

What are the consequences of rapid IV administration of a slow-distributing drug?

A
  • rapidly distrubutes in central compartment (blood, heart, brain, liver, tissues)
  • slowly distributes into peripheral compartment (fat and muscle)
  • both compartments comprise the volume distribution
    • tf initially have a high concentration in a lower volume
    • drug is eliminated from central while it distributes to peripheral
    • reaches EQB
    • after EQB, only elimination
28
Q

What is the danger of slow-distributing drugs?

A
  • peak concentration is higher than predicted by volume distribution
    • takes longer to reach the peripheral comparments and therefore is concentrated in the central compartment
  • if the drug has a narrow therapeutic index, this concentration can easily be in the toxic range
29
Q

What is the consequence of zero order elimination (enzymes are saturated)?

A
  • in single dosing, get constant elimination while the system is saturated and exponential elimination when concentration falls
  • in multpile dosing, zero order elimination prohibits reaching a steady state
    • increasing concentration doesn’t increase elimination
    • tf concentration of drug continues to rise
      • in practice, other enzyme systems take over = pseudo SS
30
Q

What causes interpatient variability?

A
  • age
  • genetic factors
  • idiosyncratic reactions
  • disease
  • drug-drug interactions
31
Q

How does age affect drug concentration?

A

reduced excretion and metabolism at extremes of age increases the half-life and persistence of some drugs - tf may need lower doses if multi-dosing

32
Q

Babies are deficient in

A

drug metabolizing enzymes, particularly phase II conjugation

tf increased plasma half life of drugs

33
Q

Elderly are deficient in

A

Cyt-p450 enzymes

increases half-life of drugs

34
Q

What genetic factors contribute to drug metabolism?

A
  • polymorphisms of enzymes (fast or slow)
  • ethnic expression eg ALDH in Chinese
35
Q

In a pharmacodynamic drug-drug interaction

A

drug A modifies the effect of drug B without affecting its concentration

36
Q

In a pharmacokinetc drug-drug interaction

A

drug A modifies the concentration of drug B at its receptor

37
Q

To be clinically significant, drug-drug interactions require

A
  • the drug affected to have a narrow tehrapeutic index
  • its concentration-response curve is steep such that small changes in concentration have large changes in effect
38
Q

Pharmacodynamic interactions can occur at

A

receptors eg antagonism; can cause physiological effects

39
Q

Pharmacokinetic interactions act at the level of

A
  • absorption
  • distribution
  • metabolism
  • excretion
40
Q

Pharmacokinetic interactions at the level of absorption

A
  • alter gastric emptying rates
    • decreased by opiates
    • increased my metaclopramide
  • formation of poorly-absorbed complexes
    • calcium & tetracyclines
41
Q

Pharmacokinetic interactions at the level of distribution

A
  • displacement from plasma protein binding sites transiently increases [unbound drug]
  • causes an increase in elimination that corrects [unbound drug]
  • overall decrease in drug, but no change in ‘free drug’ in plasma
    • eg aspirin displacing phenytoin
42
Q

Pharmacokinetic interactions at the level of metabolism

A
  • induction of p450 (rifampicin, ethanol) decreases half-life/concentration in plasma, and
    • eg warfarin
  • leads to increased bioactivation that can increase toxicity
    • eg paracetamol
  • inhibition of p450 (steroids, cimetidine) increases half-life/increases plasma concentration
    • eg phenytoin, digoxin
43
Q

Pharmacokinetic interactions at the level of excretion

A
  • alter protein binding, affecting filtration
  • alter tubular secretion (eg blocking it with probenic acid for masking)
  • alter urine flow and pH (eg using bicarb to alkalize urine to tx aspirin overdose)

General Pharmacology (1 decks)

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